Unveiling Molecular Mechanisms of Learning and Memory

1. Neuroscience: Exploring the Brain, 3e Chapter 25: Molecular Mechanisms of Learning and Memory

2. Introduction • Neurobiology of memory • Identifying where and how different types of information are stored • Hebb • Memory results from synaptic modification • Study of simple invertebrates • Synaptic alterations underlie memories (procedural) • Electrical stimulation of brain • Experimentally produce measurable synaptic alterations - dissect mechanisms

3. Procedural Learning • Procedural memories amenable to investigation • Nonassociative Learning • Habituation • Learning to ignore stimulus that lacks meaning • Sensitization • Learning to intensify response to stimuli

4. Procedural Learning • Associative Learning • Classical Conditioning: Pair an unconditional stimulus (UC) with a conditional stimulus (CS) to get a conditioned response (CR)

5. Procedural Learning • Associative Learning (Cont’d) • Instrumental Conditioning • Learn to associate a response with a meaningful stimulus, e.g., reward lever pressing for food • Complex neural circuits related to role played by motivation

6. Simple Systems: Invertebrate Models of Learning • Experimental advantages in using invertebrate nervous systems • Small nervous systems • Large neurons • Identifiable neurons • Identifiable circuits • Simple genetics

7. Simple Systems: Invertebrate Models of Learning • Nonassociative Learning in Aplysia • Gill-withdrawal reflex • Habituation

8. Simple Systems: Invertebrate Models of Learning • Nonassociative Learning in Aplysia (Cont’d) • Habituation results from presynaptic modification at L7

9. Simple Systems: Invertebrate Models of Learning • Nonassociative Learning in Aplysia (Cont’d) • Repeated electrical stimulation of a sensory neuron leads to a progressively smaller EPSP in the postsynaptic motor neuron

10. Simple Systems: Invertebrate Models of Learning • Nonassociative Learning in Aplysia (Cont’d) • Sensitization of the Gill-Withdrawal Reflex involves L29 axoaxonic synapse

11. Simple Systems: Invertebrate Models of Learning • Nonassociative Learning in Aplysia (Cont’d) • 5-HT released by L29 in response to head shock leads to G-protein coupled activation of adenylyl cyclase in sensory axon terminal. • Cyclic AMP production activates protein kinase A. • Phosphate groups attach to a potassium channel, causing it to close

12. Simple Systems: Invertebrate Models of Learning • Nonassociative Learning in Aplysia (Cont’d) • Effect of decreased potassium conductance in sensory axon terminal • More calcium ions admitted into terminal and more transmitter release

13. Simple Systems: Invertebrate Models of Learning • Associative Learning in Aplysia • Classical conditioning: CS initially produces no response but after pairing with US, causes withdrawal

14. The molecular basis for classical conditioning in Aplysia • Pairing CS and US causes greater activation of adenylyl cyclase because CS admits Ca2+ into the presynaptic terminal Simple Systems: Invertebrate Models of Learning

15. Vertebrate Models of Learning • Neural basis of memory: principles learned from invertebrate studies • Learning and memory can result from modifications of synaptic transmission • Synaptic modifications can be triggered by conversion of neural activity into intracellular second messengers • Memories can result from alterations in existing synaptic proteins

16. Vertebrate Models of Learning • Synaptic Plasticity in the Cerebellar Cortex • Cerebellum: Important site for motor learning • Anatomy of the Cerebellar Cortex • Features of Purkinje cells • Dendrites extend only into molecular layer • Cell axons synapse on deep cerebellar nuclei neurons • GABA as a neurotransmitter

17. Vertebrate Models of Learning • The structure of the cerebellar cortex

18. Cancellation of expected reafference in the electrosensory cerebellum of skates- synaptic plasticity at parallel fiber synapses. Vertebrate Models of Learning

19. Vertebrate Models of Learning • Synaptic Plasticity in the Cerebellar Cortex • Long-Term Depression in the Cerebellar Cortex

20. Vertebrate Models of Learning • Synaptic Plasticity in the Cerebellar Cortex (Cont’d) • Mechanisms of cerebellar LTD • Learning • Rise in [Ca2+]i and [Na+]i and the activation of protein kinase C • Memory • Internalized AMPA channels and depressed excitatory postsynaptic currents

21. Vertebrate Models of Learning • Synaptic Plasticity in the Cerebellar Cortex (Cont’d)

22. Vertebrate Models of Learning • Synaptic Plasticity in the Cerebellar Cortex (Cont’d)

23. Vertebrate Models of Learning • Synaptic Plasticity in the Hippocampus • LTP and LTD • Key to forming declarative memories in the brain • Bliss and Lomo • High frequency electrical stimulation of excitatory pathway • Anatomy of Hippocampus • Brain slice preparation: Study of LTD and LTP

24. Vertebrate Models of Learning • Synaptic Plasticity in the Hippocampus (Cont’d) • Anatomy of the Hippocampus

25. Vertebrate Models of Learning • Synaptic Plasticity in the Hippocampus (Cont’d) • Properties of LTP in CA1

26. Vertebrate Models of Learning • Synaptic Plasticity in the Hippocampus (Cont’d) • Mechanisms of LTP in CA1 • Glutamate receptors mediate excitatory synaptic transmission • NMDA receptors and AMPA receptors

27. Vertebrate Models of Learning • Synaptic Plasticity in the Hippocampus (Cont’d) • Long-Term Depression in CA1

28. Vertebrate Models of Learning • Synaptic Plasticity in the Hippocampus (Cont’d) • BCM theory • When the postsynaptic cell is weakly depolarized by other inputs: Active synapses undergo LTD instead of LTP • Accounts for bidirectional synaptic changes (up or down)

29. Vertebrate Models of Learning • Synaptic Plasticity in the Hippocampus (Cont’d) • LTP, LTD, and Glutamate Receptor Trafficking • Stable synaptic transmission: AMPA receptors are replaced maintaining the same number • LTD and LTP disrupt equilibrium • Bidirectional regulation of phosphorylation

30. Vertebrate Models of Learning • LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)

31. Vertebrate Models of Learning • LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)

32. Vertebrate Models of Learning • Synaptic Plasticity in the Hippocampus (Cont’d) • LTP, LTD, and Memory • Tonegawa, Silva, and colleagues • Genetic “knockout” mice • Consequences of genetic deletions (e.g., CaMK11 subunit) • Advances (temporal and spatial control) • Limitations of using genetic mutants to study LTP/learning: secondary consequences

33. The Molecular Basis of Long-Term Memory • Phosphorylation as a long term mechanism:Persistently Active Protein Kinases • Phosphorylation maintained: Kinases stay “on” • CaMKII and LTP • Molecular switch hypothesis

34. The Molecular Basis of Long-Term Memory • Protein Synthesis • Protein synthesis required for formation of long-term memory • Protein synthesis inhibitors • Deficits in learning and memory • CREB and Memory • CREB: Cyclic AMP response element binding protein

36. The Molecular Basis of Long-Term Memory • Protein Synthesis (Cont’d) • Structural Plasticity and Memory • Long-term memory associated with transcription and formation of new synapses • Rat in complex environment: Shows increase in number of neuron synapses by about 25%

37. Concluding Remarks • Learning and memory • Occur at synapses • Unique features of Ca2+ • Critical for neurotransmitter secretion and muscle contraction, every form of synaptic plasticity • Charge-carrying ion plus a potent second messenger • Can couple electrical activity with long-term changes in brain

38. End of Presentation

39. Simple Systems: Invertebrate Models of Learning • The molecular basis for classical conditioning in Aplysia • Pairing CS and US causes greater activation of adenylyl cyclase because CS admits Ca2+ into the presynaptic terminal

40. Simple Systems: Invertebrate Models of Learning • Associative Learning in Aplysia • Classical conditioning: CS initially produces no response but after pairing with US, causes withdrawal

41. Vertebrate Models of Learning • Synaptic Plasticity in Human area IT